Pharmaceuticals which enhance the neurotransmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological means which caused them to possess numerous undesired side-effects. The more recently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors which suppress the firing activity of 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients. (See, e.g., Le Poul et al., Arch. Pharmacol., 352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5HT1A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al., Trends Neurosci., 19:378-383 (1996), suggest a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concommitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
Compounds having antidepressant and anxiolytic activity due to their affinity for the 5HT1A autoreceptors are disclosed in, e.g., U.S. Pat. No. 3,717,634 which claims N-(heteroarcyclic)-piperazinylalkyl derivatives of azaspiroalkanediones Aryl and heteroaryl piperazinylalkyl carboxamides having 5HT1A activity are disclosed, e.g., in U.S. Pat. Nos. 5,106,849; 5,278,160; and 5,482,940.
Glutarimide derivatives having anxiolytic and antihypertensive activity are disclosed in U.S. Pat. No. 4,612,312.
Benzoxazine and thiazine derivatives useful for treating psychotic disorders and schizophrenia are disclosed in PCT Patent Application Publication No. WO 8907596-A. However, none of these patents disclose compounds which act at both the 5HT1A autoreceptors and the 5-HT-transporter.